This R21 application is in response to the program announcement NOT-03-080. Older adults are the population at greatest risk of disease and death from a bioterrorism attack. Older adults experience 95% of the morbidity and mortality due to naturally occurring influenza, a Category C bioterrorist organism, largely due to immune senescence. Although vaccination effectively reduces influenza morbidity and mortality, elderly people are less protected by vaccination compared to their younger counterparts, and are likely to be similarly handicapped in the event of a bioterrorist attack with influenza (or other infectious agents). The purpose of this study is to evaluate a novel booster vaccination strategy for enhancing vaccine efficacy using the influenza model. Our general hypothesis is that the decline in vaccine efficacy is due to the age-related decline in responsiveness or functionality of influenza-specific T cells, specifically, type I T helper cells (Thl). To test our hypothesis, we propose the following two Specific Aims: 1) To quantify Thl response to influenza vaccination in healthy elderly and young subjects, and correlate it with antibody response. Our working hypothesis is that there is a direct correlation between Thl and antibody response, particularly IgG1, to influenza vaccination. Thl T cell response to influenza vaccination will be quantified by enumerating influenza-specific Thl (IS-Thl) using intracellular cytokine staining of interferon-gamma (IFN-gamma) in peripheral blood mononuclear cells (PBMC) activated ex vivo by influenza virus. The antibody response will be determined by hemagglutination-inhibition assay (HI), microneutralization assay, and IgG subtypes IgG1-3 measured by ELISA. 2) To examine the safety and immunogenicity of two vaccination strategies to enhance the Thl response: with CpG ODN adjuvant and by booster at the peak of lS-Thl expansion following initial vaccination. Elderly people are known to produce less antibody to influenza vaccination than their younger counterparts. We hypothesize that this can be corrected, at lease in part, by using either the Thl-biased adjuvant CpG ODN or a booster vaccine; and that this booster vaccine is more effective when given at when the IS-Thl are most abundant in circulating blood after the initial influenza vaccination. In this pilot study, we will compare the T cell and antibody responses in elderly and young subjects with or without CpG ODN or a booster vaccination given either on day 7 (peak of Thl expansion) or 28 (end of Thl expansion) after the initial vaccination. We believe this pilot study will provide valuable preliminary information on the role of Thl dysfunction in immune senescence and on our novel vaccination strategies targeting the elderly population. Information from this study will also have great implication on strategy for protecting elderly population against other bioterrorist attack.